Urinary incontinence is any involuntary leakage of urine and can be categorized into five types based on the pattern of symptoms including urge incontinence, stress incontinence, overflow incontinence, functional incontinence, and mixed incontinence. Current pharmacological management of urinary incontinence includes muscarinic receptor antagonists such as oxybutynin, tolterodine, trospium, solifenacin, and darifenacin. Lam and Hilas, Clinical Interventions in Aging (2007), 2(3), 337-345. However, these anticholinergic drugs are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma, and have possible anticholinergic side effects such as heat prostration, dry mouth, constipation, dry eyes, urinary retention, dizziness and blurred vision.
(±)-4-Amino-3-(4-chlorophenyl)butanoic acid (baclofen) is an analog of gamma-aminobutyric acid (i.e., GABA) that selectively activates GABAB receptors, resulting in neuronal hyperpolarization. GABAB receptors are located in laminae I-IV of the spinal cord, where primary sensory fibers end. These G-protein coupled receptors activate conductance by K+-selective ion channels and can reduce currents mediated by Ca2+ channels in certain neurons. Baclofen has a presynaptic inhibitory effect on the release of excitatory neurotransmitters and also acts postsynaptically to decrease motor neuron firing. Bowery, Trends Pharmacol. Sci. (1989), 10, 401-407: and Misgeld et al., Prog. Neurobiol. (1995), 46, 423-462. In a double blind crossover trial baclofen administered at a dose of 5 mg four times per day was shown to significantly improve diurnal and nocturnal of frequency of micturition and the severity of incontinence in patients with unstable bladder syndrome. Taylor and Bates, British J Urology (1979), 51, 504-505.
Recently, prodrugs of (R)-baclofen that are well absorbed in the large intestine/colon, and hence suitable for oral sustained release formulations, have been developed. Gallop et al., U.S. Pat. Nos. 7,109,239, 7,227,028, 7,300,131, and 7,572,830; Leung et al., US 2008/0206332: Cundy, US 2009/0041806: and Sastry et al., US 2009/0197958: each of which is incorporated by reference herein in its entirety. For example, (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid, (1),
a prodrug of (R)-baclofen, exhibits high bioavailability as (R)-baclofen when dosed either orally or directly into the colon of a mammal. Gallop et al., U.S. Pat. No. 7,109,239: and Lal et al., J Pharmacol Experimental Therapeutics (2009), 330(3), 911-921.